Ionic liquids (ILs) have been the subject of considerable interest as media for a wide range of synthetic and analytical processes.(1, 2) They are considered in a ‘green chemistry’ context due to their low vapour pressure, ease of recovery facilitating recycling (3) and applicability to catalytic processes.(4) ILs are characterized by a melting point below 100° C. ILs possess a number of interesting properties such as high polarity and ionic conductivity, a wide window of electrochemical potential and excellent chemical and thermal stability to a wide range of chemicals even at high temperatures. However, it is this stability that has led to questions as to the potential for ILs to accumulate in the environment over time.(5) Ionic liquids may cause problems either from premature degradation or environmental persistence, with the result that when the ionic liquid has served its operational use, disposal becomes an issue. As the pressure to reduce incineration and landfill waste increases, so the requirement for chemicals which are biodegradable also increases.(6) Within the field of green chemistry it is unacceptable to produce large quantities of waste which have high ecotoxicity or biological activity.(7) Seddon reported the first industrial process where ionic liquids were used on a multi-tonne scale.(8) As ionic liquids advance from academic curiosities the need to consider their toxicity and biodegradation is paramount before processes using ionic liquids are scaled up.
Although there has been intense interest in the use of ionic liquids (ILs) (FIG. 1) as green solvents, relatively little is known about their biodegradability and toxicity, which are basic properties in the environmental risk assessment of any organic compound.
The biodegradability of the ILs can be evaluated applying the following standard methods: (i) Sturm Test (ii) Closed Bottle Test (OECD 301D) (iii) CO2 Headspace Test (ISO 14593). Both tests (ii) and (iii) are included in the European Regulation (EC) No 648/2004 of biodegradability of detergent surfactants, the CO2 Headspace Test being the reference method for laboratory testing of ultimate biodegradability. In the Closed Bottle and CO2 Headspace tests, the compound to be evaluated is added to an aerobic aqueous medium inoculated with wastewater microorganisms and the depletion of dissolved O2 or the CO2 evolution is measured periodically and reported as a percentage of theoretical maximum. Sodium n-dodecyl sulfate (SDS) is generally used as a reference substance.
An IL will be considered “readily biodegradable” and, therefore it will be assumed that such a chemical will be rapidly and completely biodegraded in an aquatic environment under aerobic conditions, if the biodegradation level measured according to one of the described tests is higher than 60% within 28 days.
IL toxicity tests are based on systems with different biological complexity levels. The toxicity of the ILs has been measured on a wide range of organisms from bacteria and fungi, to higher organisms such as zebrafish, the soil nematode and the freshwater snail. LC50, IC50, EC50 and MIC values are used as a measurement of the toxicity of the ILs on the organism. Growth inhibition studies have also been carried out on algae and terrestrial plants. Such tests indicate the levels at which the IL in a biological system prevents or disrupts growth. Data from such studies on ILs can then be compared to well known values for common organic solvents. In general the toxicity of ionic liquids tested to date is found to be some orders of magnitude higher than that of conventional solvents such as acetone and methanol. A common problem with the toxicity of ionic liquids is associated with the presence of an extended hydrocarbon chain. The length of the side chains was found to influence the dialkylimidazolium ionic liquid's toxicity, with longer chain length proving to be more toxic. In fact, Bodor et al. (9) have shown that the long chain ester derivatives of methyl imidazole (shown as compound 6 in FIG. 3) show effective antimicrobial activity at ppm concentrations, clearly demonstrating the toxic effect of such ILs on microbes.
In 1991, Howard et al, (10) published a report on the development of a model for predicting aerobic biodegradability of organic compounds based on chemical structure alone. Organic compounds having certain structural fragments known or thought to have an impact on biodegradability were examined, e.g., addition of an ester functional group is known to generally increase biodegradability. Excellent predictive results for many of the compounds were achieved. However, interestingly, certain compounds, include certain aliphatic ethers were incorrectly predicted to biodegrade quickly.
In 1996, Boethling reported that over 40 years of studies had shown that relatively small changes in molecular structure can appreciably alter a chemical's susceptibility to biodegradation. Such studies have resulted in several “rules of thumb” about effects of chemical structure on biodegradability. These rules included that molecular features such as e.g., halogens, chain branching, nitro groups, heterocyclic residues and aliphatic ethers all generally lead to increased resistance to aerobic biodegradability (10).
In 2002, Gathergood and Scammells conducted the first study of IL biodegradability, based on investigations into effects of substituents on the biodegradability of ILs containing a dialkylimidazolium cation (11). (FIG. 1) Nitrogen-containing heterocycles were already known to be difficult groups for degradation by microorganisms (9). Gathergood and Scammells found that the combination of features of an imidazolium cation core, an anion such as Br−, BF4−, PF6−, NTf2− or N(CN)2−, and an unsubstituted linear alkyl ester or alkyl amide side chain (ethyl-octyl) furnished ILs which were for the most part, liquid at room temperature. A limited number of these compounds were shown to evolve CO2 in the region of 48-60% when subjected to the Sturm biodegradability test (ISO9439: a pass being 60% evolution, 80% evolution deemed “readily biodegradable”).
In 2004, Gathergood, Scammells and Garcia (11) produced imidazolium ILs using standard methods for imidazolium ILs which involved alkylation of methyl imidazole with the appropriate alkyl esters or amide derivates of bromoacetic acid. Counterion exchange procedures allowed introduction of alternative counterions and formation of the ILs in good yield. Biodegradability was assessed using the “Closed Bottle Test” (OECD 301D) against sodium dodecyl sulfate as reference wherein a biodegradability result greater than 60% for tested compounds means the compound is deemed “readily biodegradable”. Gathergood and Garcia reported that the commonly used dialkylimidazolium ILs (BmimX) showed negligible biodegradability (in the range of 0-2% degradation over 28 days) in the Closed Bottle Test. However, the incorporation of an ester in the side chain of the imidazolium cation significantly increased biodegradability over BmimXs, whereas incorporation of an amide in the side chain showed a far lesser biodegradability effect, however the results still fell far short of 60% biodegradability within 28 days. 3-Methyl-1-(pentoxycarbonylmethyl) imidazolium bromide proved to be the most biodegradable compound in this series, giving a result of just 32% degradation after 28 days. Gathergood and Garcia also showed that the biodegradability increased slightly with increasing alkyl side chain length for the lowest alkyl esters and later remained relatively constant, with ester of chain length greater than 4 proving to be the most biodegradable. It was postulated that enzymatic cleavage of the ester bond led to easily metabolized fragments. In this paper the authors briefly identified the negative effect compound toxicity may have on biodegradability, since many quaternary ammonium salts are known to be potential biocides and so a discussion was presented that certain ILs may inhibit the growth of biodegrading microorganisms. Clearly, it is desirable to produce ILs that are less toxic to biodegrading microorganisms.
Other groups have examined IL toxicology (12) and it has been found that the length of alkyl chain affects the biological properties of such molecules, with longer alkyl chains associated with higher toxicity. As previously mentioned, one particular compound containing an ester group in the side chain of an imidazolium salt has a clear-cut toxic effect and indeed has been shown to be a potent antibacterial (9) (see FIG. 3 for a structural comparison). In this case Bodor designed the chemical as part of a medicinal chemistry project to make use of the biological activity of this class of compounds.
Later in 2004, Gathergood, Scammells and Garcia (11) looked at the effect of the counter anion and the alkyl chain length on biodegradability and toxicology of the imidazolium based ILs as compared to BmimBr analogues. Counter anions such as Br−, BF4−, PF6−, NTf2−, N(CN)2− and octylOSO3− were examined. An IL comprising an octylsulfate anion and alkyl ester side chain showed the highest biodegradability according to the Closed Bottle Test (49% biodegradation after 28 days) as compared to commonly used ILs, BmimBF4 and BmimPF6, which proved to be poorly biodegradable.
However, it must be noted that none of the disclosed compounds in any of these studies could be classified as “readily biodegradable”. Bioassay aquatic toxicity tests on freshwater crustacea and saltwater bacteria showed that toxicity of the tested ILs became more pronounced with increasing alkyl chain length. Toxicity was far more pronounced than with organic solvents such as acetone, acetonitrile and even chlorinated solvents, yet lower than for cationic surfactants. It was also shown that as the chain length increases, the difference in toxicity between the ILs and cationic surfactants decreases significantly. It was proposed that the crucial factor in relation to aquatic toxicity was the length of the alkyl side chain, the inorganic counter anion having only a small effect.
More recently still, Gathergood, Scammells and Garcia reported the first ILs which were classifiable as “readily biodegradable” under aerobic conditions using the “Closed Bottle Test” (OECD 301D) and the “CO2 Headspace Test” (ISO 14593) (11, 13, 14). Furthermore, investigations were directed to the nature of the effect of the addition of a 2-methyl group to the imidazole unit of the IL. 2-Methyl substitution was considered to have potential benefits in increasing biodegradability, since the addition of such an electron donating group should activate the ring to attack, and also should overcome the tendency of ILs containing an imidazole ring to form carbenes, where carbene formation is undesirable. 1-Alkoxycarbonyl-3-methylimidazolium cations and 1-alkoxycarbonyl-2,3-dimethylimidazolium analogues were tested. Surprisingly, the addition of the 2-methyl group to the IL had no significant effect on the biodegradation results. Interestingly, the CO2 Headspace Test data were consistent with the Closed Bottle Test and in fact, provided biodegradability results in the range 60-67% for particular ILs containing both an ester group in the side chain and octylsulfate as counter ion. The higher results compared to those of the Closed Bottle Tests are thought to be related to differences in the cell density of the tests. The results allow a family of ILs to be classified as “readily biodegradable” for the first time, in other words it can be assumed that the particular ILs will be rapidly mineralised/biodegraded in aquatic environments under aerobic conditions. Finally, the possibility of an inhibitory effect of BmimX compounds on aerobic microorganisms was investigated and no toxic effect was shown at the test concentrations. The concentrations screened for antibacterial activity are generally from 2 μg/ml to 1000 μg/ml. Potent antibacterials will have MIC values at the lower end of this range, while compounds which have MIC values at the higher end of the range, show antibacterial activity but not at levels significant for antibacterial drug development. IL compounds displaying a lack antibacterial activity at levels of up to 20000 μg/ml, would be most desirable. At these high concentrations a lack of antibacterial activity would be a significant result.
Green solvents find one use in the field of transition metal catalysis, where one of the principal present day difficulties is the inefficient recycling and reuse of costly catalysts and ligands. Where economically efficient catalysts are used, selectivity is usually poor and elaborate poisons or conditions are needed to improve the result (15). Due to the physico-chemical properties of ILs, compared with those of organic and aqueous media, they provide a means of catalyst immobilization (16). The non-nucleophilic nature bestows an inert reaction medium that can also provide an extension of the catalyst lifetime (17). Low-polarity compounds, for example diethyl ether and n-hexane, are commonly insoluble in ILs. This varying solubility of the aforementioned organic solvents and ILs provides a suitable environment for biphasic catalysis. The positive aspects of homogeneous and heterogeneous catalysis are combined using a biphasic system. In this phase system, the catalyst resides in the IL and the substrates/products reside in the alternate phase. This system can implement a cost-effective way to successfully separate the desired product by simple decantation, leaving the catalyst immobilised in the IL, equipped for reuse. In the case of monophase catalysis in ILs, where the substrates are soluble in the IL medium, simple extraction or indeed facile distillation, due to the low vapour pressure of the IL, can be utilised as an alternative method for separating products from the IL/catalyst system.
Many common ILs have been investigated as alternative solvents for catalytic hydrogenations. Of these studies, the greater part focuses on the common commercially available ILs of the form RMim+ (R: alkyl chain) X− (18). (FIG. 1)
Palladium on Carbon is well known as a universal catalyst for olefin hydrogenation, however its efficient catalytic activity may lead to poor selectivity. Thus it is desirable to provide alternative green solvents which may be used in organic reactions, such as hydrogenation reactions for example. Of particular interest are such solvents which may be used in hydrogenation of compounds such as trans-cinnamaldehyde or benzyl cinnamate using the commercially available Pd/C catalyst and which will allow superior control of the conversion and selectivity.
Thus, it is desired to assist in the development of green methods for drug manufacture in the chemical industry through the provision of a series of “readily biodegradable” ionic liquid solvents (ILs) for use in chemical synthesis which are non-toxic or show a reduced toxicity when compared to more traditional ionic liquid solvents. Such biodegradable and non-toxic ionic liquid solvents are highly desirable since producing less waste leads to cost savings in disposal, and a more environmentally friendly profile for the company.
It is desirable to combine desirable solvent properties such biodegradability and coordination ability in a solvent that can be tailored to the specific needs of a reactions, for example, enhanced conversion and/or selectivity of product. The ionic liquids in the present invention allow such solvent tailoring.
Further desirable is the provision of a designer library of ionic liquid solvents that possess these characteristics and yet are economically viable, robust and ideally suited to the preparation of drugs. The ionic liquids of the invention yield an excellent commercial source for tunable achiral coordinating, biodegradable and non-toxic solvents.
Furthermore, ionic liquids have been recognized as important solvents for biomass dissolution, because in most cases conventional liquids are incapable of dissolving a variety of important biomolecules, including biopolymers such as cellulose, silk, wool and other forms of keratin (1). Smaller carbohydrate oligomers as well as polymeric carbohydrates can also be solubilised by appropriate ionic liquid (1). It is highly desirable therefore to use non-toxic and/or biodegradable ionic liquids for biomass dissolution.